DESCRIPTION: Apoptosis is emerging as a type of cell death with characteristic morphology that contributes to neuronal loss during normal development and in pathologic situations, including Alzheimer disease (AD), Huntington disease, stroke and seizure. Despite increasing interest in the process, few details concerning the molecular mechanisms of neuronal apoptosis are known. We previously identified a temporal cascade of gene induction in sympathetic neurons undergoing apoptosis because of nerve growth factor (NGF) deprivation and showed that the protein product of one induced gene, c-Jun, was necessary for death. In cortical neurons, apoptosis induced by AD amyloid b-protein (Ab) treatment is accompanied by a genetic cascade that is strikingly similar to that identified previously, including a robust c-jun induction. Since (i) c-jun mRNA is induced during neuronal apoptosis initiated by either Ab-treatment or NGF deprivation, (ii) this c-jun mRNA appears to form functional c-Jun protein in both model systems, as discerned by the subsequent activation of "downstream" genes, and (iii) c-Jun is necessary for apoptosis after NGF deprivation, our current working hypothesis is that events which lead up to, modulate, and include the induction of c-jun are necessary for Ab-induced neuronal death. In pursuit of this hypothesis, we propose to (i) compare and contrast patterns of gene expression in neurons undergoing apoptosis as a result of Ab -treatment of NGF-deprivation; (ii) define the role of c-Jun in Ab -induced neuronal apoptosis by using microinjected, neutralizing antibodies and ectopic expression of a dominant negative form of c-Jun; (iii) elucidate the mechanism(s) leading to c-jun induction in Ab-treated neurons, with particular emphasis on the role of oxidative stress; (iv) explore a possible mechanism of c-Jun action by analyzing Ab -treated neurons for markers of cell cycle re-entry, including patterns of c-Jun heterodimer formation; (v) compare the patterns of neuronal apoptosis and "apoptotic" gene expression in AD and control brain tissue to discern whether this genetic cascade may contribute to neuronal loss in vivo. These studies will evaluate the hypotheses that Ab -induced neuronal death is critically dependent on altered gene expression, that oxidative stress is central to these genetic events, and that this genetic cascade may contribute to neuronal loss in vivo in AD. Hence, this work will further our long-term goals of elucidating the mechanisms underlying neuronal death, and, ultimately, identifying pharmacologic means to prevent this death.